`Filed on behalf of: Patent Owner Illumina Cambridge Ltd.
`By:
`
`Lead Counsel:
`Robert A. Lawler
`REINHART BOERNER VAN
`DEUREN S.C.
`22 East Mifflin Street, Suite 600
`Madison, WI 53703
`Tel.: 608-229-2217
`Fax: 608-229-2100
`Email: rlawler@reinhartlaw.com
`
`Filed: ____________
`
`Backup Counsel:
`Brenton R. Babcock
`William R. Zimmerman
`(admitted pro hac vice)
`Jonathan E. Bachand
`KNOBBE, MARTENS, OLSON &
`BEAR, LLP
`2040 Main Street, 14th Floor
`Irvine, CA 92614
`Tel.: (949) 760-0404
`Fax: (949) 760-9502
`Email: BoxIllumina@knobbe.com
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`
`
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`
`INTELLIGENT BIO-SYSTEMS, INC.
`Petitioner,
`
`v.
`
`
`
`
`
`ILLUMINA CAMBRIDGE LTD.
`Patent Owner.
`
`
`
`
`Case IPR2013-00517
`U.S. Patent 7,566,537
`
`
`
`
`
`
`
`14786992
`
`
`
`
`
`
`ILLUMINA’S PATENT OWNER RESPONSE
`
`May 5, 2014
`
`Columbia Ex. 2011
`Illumina, Inc. v. The Trustees
`of Columbia University
`in the City of New York
`IPR2020-01177
`
`
`
`
`Filed on behalf of: Patent Owner Illumina Cambridge Ltd.
`By:
`
`Lead Counsel:
`Robert A. Lawler
`REINHART BOERNER VAN
`DEUREN S.C.
`22 East Mifflin Street, Suite 600
`Madison, WI 53703
`Tel.: 608-229-2217
`Fax: 608-229-2100
`Email: rlawler@reinhartlaw.com
`
`Filed: ____________
`
`Backup Counsel:
`Brenton R. Babcock
`William R. Zimmerman
`(admitted pro hac vice)
`Jonathan E. Bachand
`KNOBBE, MARTENS, OLSON &
`BEAR, LLP
`2040 Main Street, 14th Floor
`Irvine, CA 92614
`Tel.: (949) 760-0404
`Fax: (949) 760-9502
`Email: BoxIllumina@knobbe.com
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`
`
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`
`INTELLIGENT BIO-SYSTEMS, INC.
`Petitioner,
`
`v.
`
`
`
`
`
`ILLUMINA CAMBRIDGE LTD.
`Patent Owner.
`
`
`
`
`Case IPR2013-00517
`U.S. Patent 7,566,537
`
`
`
`
`
`
`
`14786992
`
`
`
`
`
`
`ILLUMINA’S PATENT OWNER RESPONSE
`
`May 5, 2014
`
`
`
`
`
`TABLE OF CONTENTS
`
`Page No.
`
`
`I.
`II.
`
`Introduction ...................................................................................................... 1
`Illumina’s Claimed Invention Includes a Novel, not Previously
`Considered 3’-OH Protecting Group for SBS ................................................. 4
`III. The Law of Nonobviousness ........................................................................... 8
`IV. The Person Of Ordinary Skill in the Art ......................................................... 9
`V. Grounds Of This Proceeding ......................................................................... 10
`VI. Tsien’s 3’-Azido Group Cannot Be Removed To Expose A 3’-OH
`Group ............................................................................................................. 11
`VII. Tsien’s Three 3’-Blocking Group Criteria Are Incompatible With
`Zavgorodny’s Azidomethyl Ether And Removal Conditions ....................... 12
`A Person Of Ordinary Skill In The Art Would Not Have
`1.
`Expected Zavgorodny’s Azidomethyl Group To Be Accurately
`Or Efficiently Incorporated By A Polymerase .................................... 14
`The Prior Art Teaches That The Electrophilic
`a.
`Characteristics Of An Azido Group Would React
`With Strong Nucleophiles In The Polymerase Active
`Site ............................................................................................. 15
`Removable 3’-O-Protecting Groups Were Known
`To Interfere With Accurate And Efficient
`Polymerase Incorporation ......................................................... 16
`A Person of Ordinary Skill In The Art Would Not Have
`Expected Zavgorodny’s Removal Conditions To Meet Tsien’s
`Requirement for Mild, Rapid, and Quantitative Deblocking .............. 18
`Zavgorodny’s Removal Conditions Are
`a.
`“Triphenylphosphine In Aqueous Pyridine At 20 oC” ............. 18
`Zavgorodny’s Aqueous Pyridine Removal
`Conditions Would Denature DNA And, Thus,
`
`2.
`
`b.
`
`b.
`
`14786992
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`-i-
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`
`c.
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`
`
`3.
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`
`14786992
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`-ii-
`
`Cannot Be “Mild” Within The Context Of Tsien’s
`DNA Sequencing Method ......................................................... 19
`Zavgorodny’s Removal Conditions Using Pyridine
`i.
`Would Denature The DNA In Tsien’s Sequencing
`Method ............................................................................ 19
`Zavgorodny’s “Mild” Conditions Would Not Have
`Been “Mild” In The Context Of Tsien’s DNA
`Sequencing Method ........................................................ 21
`Zavgorodny’s Removal Conditions Would Not Have
`Been Expected To Be Quantitative Or Rapid ........................... 23
`Loubinoux’s Phenolic Azidomethyl Ether
`i.
`Removal Efficiency Of 60-80% Provides An
`Expectation That Zavgorodny’s Aliphatic
`Azidomethyl Ether Would Not Cleave
`Quantitatively ................................................................. 24
`The Prior Art Repeatedly Reports Non-
`Quantitative Azido Conversion Using
`Triphenylphosphine In Pyridine And Water, And
`Provides An Expectation That Zavgorodny’s
`Azidomethyl Ether Removal Conditions Would
`Not Be Quantitative ........................................................ 26
`The Prior Art Data Indicates That Azido To Amino
`Conversion Using Triphenylphosphine In Pyridine
`And Water Would Not Proceed Rapidly ........................ 29
`Zavgorody’s Removal Conditions Do Not Meet
`Tsien’s Requirements For Quantitative And Rapid
`Cleavage ......................................................................... 30
`A Person of Ordinary Skill In The Art Would Not Have
`Expected Zavgorodny’s Azidomethyl Ether To Permit A
`Polymerase to Reinitiate Synthesis Subsequent To Deblocking ........ 31
`
`ii.
`
`ii.
`
`iii.
`
`iv.
`
`
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`
`
`a.
`
`b.
`
`3’-O-Protecting Groups Can Reinitiate DNA
`Synthesis Before (Not After) Deblocking ................................ 31
`Zavgorodny’s Removal Conditions Use Pyridine,
`Which Would Interfere With Reinitiation Of DNA
`Synthesis ................................................................................... 32
`VIII. Ju’s Protecting Group Requirements Are Incompatible With
`Zavgorodny’s Azidomethyl Group And Removal Conditions ..................... 33
`Zavgorodny’s Azidomethyl Group Is Precisely The Type Of
`1.
`Electrophilic Group That Ju Teaches Is Unsuitable For DNA
`Sequencing .......................................................................................... 35
`A Person of Ordinary Skill In The Art Would Not Have
`Expected Zavgorodny’s Azidomethyl Ether To Be Efficiently
`Incorporated By A Polymerase ........................................................... 36
`A Person of Ordinary Skill In The Art Would Not Have
`Expected Zavgorodny’s Azidomethyl Group To Be Removed
`Efficiently Enough To Satisfy Ju’s Sequencing Methods .................. 38
`A Person of Ordinary Skill In The Art Would Have Expected
`Zavgorodny’s Pyridine Solution To Denature DNA, And
`Therefore Be Incompatible With Ju .................................................... 40
`IBS’s Petition Distorts Dr. Liu’s Testimony ....................................... 40
`Claims 1-6 And 8 Of The ’537 Patent Are Nonobvious Over
`The Combination Of Ju And Zavgorody ............................................ 42
`IX. Claim 3 Is Nonobvious Over Tsien, Zavgorodny, and Prober ...................... 42
`The Claims are Not Obvious in Light of the Secondary Considerations
`X.
`of Nonobviousness......................................................................................... 43
`Illumina’s 3’-O-Azidomethyl Protecting Groups For Labeled
`1.
`Nucleotides Met a Long-Felt, Unmet Need ........................................ 44
`
`2.
`
`3.
`
`4.
`
`5.
`6.
`
`
`14786992
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`-iii-
`
`
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`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`
`
`2.
`
`Illumina’s 3’-O-Azidomethyl Group Performs Unexpectedly
`Better Than Other Protecting Groups ................................................. 49
`Illumina’s 3’-O-Azidomethyl Protecting Group
`a.
`Performs Unexpectedly Better Than The 3’-O-Allyl
`Protecting Group ....................................................................... 51
`Illumina’s 3’-O-Azidomethyl Protecting Group
`Performs Unexpectedly Better Than The Expected
`Combination of Tsien or Ju with Zavgorodny .......................... 54
`Copying Of Illumina’s 3’-O-Azidomethyl Group By IBS And
`Others Provides Objective Evidence Of Nonobviousness .................. 55
`Praise by Others ................................................................................... 59
`4.
`XI. Conclusion ..................................................................................................... 60
`
`
`b.
`
`3.
`
`
`14786992
`
`-iv-
`
`
`
`TABLE OF AUTHORITIES
`
`
`
`ActiveVideo Networks, Inc. v. Verizon Commuc’ns, Inc.,
`694 F.3d 1312 (Fed. Cir. 2012) ....................................................................... 8
`
`Page No(s).
`
`In re Boesch,
`617 F.2d 272 (C.C.P.A. 1980) ....................................................................... 48
`
`Custom Accessories, Inc. v. Jeffery-Allan Indus., Inc.,
`807 F.2d 955 (Fed. Cir. 1986) ....................................................................... 43
`
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) ................................................... 16, 29, 33, 36
`
`Eisai Co. v. Dr. Reddy’s Labs., Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) ..............................................................passim
`
`In re Fritch,
`972 F.2d 1260 (Fed. Cir. 1992) ..................................................................... 43
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................... 8, 9, 10
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) ..................................................................... 47
`
`In re ICON Health & Fitness, Inc.,
`496 F.3d 1374 (Fed. Cir. 2007) ......................................................... 21, 29, 40
`
`Institut Pasteur v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) ..............................................................passim
`
`Iron Grip Barbell Co. v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) ..................................................................... 47
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007)..................................................................................... 8, 9
`
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) ............................................................... 30, 41
`
`14786992
`
`-v-
`
`
`
`TABLE OF AUTHORITIES
`(cont’d)
`
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ..................................................... 7, 43, 44, 46
`
`Page No(s).
`
`Life Techs., Inc. v. Clontech Lab., Inc.,
`224 F.3d 1320 (Fed. Cir. 2000) ..................................................................... 41
`
`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988) ....................................................................... 41
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) ............................................................... 30, 41
`
`Panduit Corp. v. Dennison Mfg. Co.,
`810 F.2d 1561 (Fed. Cir. 1987) ..................................................................... 35
`
`In re Papesch,
`315 F.2d 381 (C.C.P.A. 1963) ....................................................................... 47
`
`Procter and Gamble Co. v Teva Pharms. USA,
`566 F.3d 989 (Fed. Cir. 2009) ....................................................................... 44
`
`Rambus Inc. v. Rea,
`731 F.3d 1248 (Fed. Cir. 2013) ..................................................................... 47
`
`Rohm & Haas Co. v. Brotech Corp.,
`127 F.3d 1089 (Fed. Cir. 1997) ..................................................................... 28
`
`Standard Oil Co. v. Am. Cyanamid Co.,
`774 F.2d 448 (Fed. Cir. 1985) ....................................................................... 41
`
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) ..................................................................... 44
`
`United States v. Adams,
`383 U.S. 39 (1966) ......................................................................................... 16
`
`W.L. Gore & Assocs., Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) ....................................................................... 9
`
`
`14786992
`
`-vi-
`
`
`
`TABLE OF AUTHORITIES
`(cont’d)
`
`
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) ..................................................................... 52
`
`Page No(s).
`
`
`
`OTHER AUTHORITIES
`
`35 U.S.C. § 103 .................................................................................................... 8, 10
`
`35 U.S.C. § 316 ............................................................................................ 1, 3, 8, 42
`
`Fed. R. Evid. 705 ..................................................................................................... 28
`
`37 C.F.R. § 42.65 ..................................................................................................... 28
`
`37 C.F.R. § 42.120 ..................................................................................................... 1
`
`
`
`
`14786992
`
`-vii-
`
`
`
`IPR2013-00517
`IBS v. Illumina
`
`
`Pursuant to 35 U.S.C. § 316(a)(8) and 37 C.F.R. § 42.120, Illumina
`
`Cambridge Ltd. (“Illumina”) responds to the Revised Petition (Paper 7) filed by
`
`Intelligent Bio-Systems, Inc. (“IBS”) regarding Claims 1-6 and 8 of U.S. Patent
`
`No. 7,566,537 (“the ’537 Patent”).
`
`I.
`
`Introduction
`
`Illumina is recognized as the undisputed leader and innovator in the DNA
`
`sequencing industry. Illumina has been referred to as the “smartest company in the
`
`world” because it “commercializes a truly innovative technology” and causes
`
`competitors “to refine or rethink their strategies.” MIT Tech. Review, 117:2 & 27-
`
`29 (2014) (Ex. 2004). Illumina’s novel and successful methods of labeling nucleic
`
`acid molecules for DNA sequencing use a reversible 3’-O-azidomethyl ether
`
`protecting group—a technology subsequently adopted by others, including IBS.
`
`See Document 71, IBS’s Answer ¶ 24, Columbia v. Illumina, No. 12-CV-00376
`
`(D. Del) (admitting that IBS uses Illumina’s azido terminator) (Ex. 2005).
`
`Indeed, where Illumina has succeeded, IBS has failed. For example, prior to
`
`adopting Illumina’s technology, IBS’s reversible terminator technology was not
`
`commercially viable and could not compete with Illumina’s 3’-O-azidomethyl
`
`nucleotides. See Interview of Qiagen’s1 Dietrich Hauffe, Genomeweb, July 17,
`
`
`1 Qiagen acquired IBS in June of 2012.
`
`14786992
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`IPR2013-00517
`IBS v. Illumina
`
`2013 (admitting that Qiagen “needed to change pretty much everything” that IBS
`
`had been working on; “the chemistry has changed, the mechanics have changed,
`
`the flow path has changed;” and admitting that “We are not HiSeq2 competitive,
`
`that’s for sure.”) (Ex. 2084). After failing to develop its own technology, IBS now
`
`seeks to reap the benefits of Ilumina’s labeling methods and reversible azido
`
`terminator technology before it is dedicated to the public.
`
`IBS’s petition asserts that DNA sequencing using nucleotides with reversible
`
`azido protecting groups is obvious, yet IBS’s own recent arguments to the Patent
`
`Office in its pending patent applications assert the nonobviousness of such
`
`methods. For example, in response to an Examiner asserting that it would have
`
`been obvious to combine Dower, which teaches DNA sequencing methods, with
`
`Seo et al. or Zavgorodny et al. (2000), which allegedly teach 3’-OH azido and 3’-
`
`OH azidomethyl groups, IBS argued that “there is no basis for the combination” of
`
`these references. See U.S. Appl. No. 13/305,415, Response to Office Action at 9,
`
`filed Nov. 12, 2013 (Ex. 2006). IBS has also repeatedly claimed DNA sequencing
`
`methods using azido and azidomethyl protecting groups. See U.S. 2012/0052489 at
`
`Claims 4-5 (Ex. 2007); U.S. 2011/0124054 at Claims 3-4 & 21-22 (Ex. 2008); U.S.
`
`
`2 The HiSeq instrument is Ilumina’s flagship DNA sequencing instrument and, like
`
`all of Illumina’s sequencers, uses 3’-O-azidomethyl protected nucleotides.
`
`
`
`-2-
`
`
`
`IPR2013-00517
`IBS v. Illumina
`
`2010/0159531 at Claims 12-13 (Ex. 2009). The Board should reject IBS’s petition
`
`inspired arguments that contradict its previous positions before the Patent Office.
`
`IBS fails to carry its burden of proving that Claims 1-6 and 8 of the ’537
`
`Patent would have been obvious to a person of ordinary skill in the art at the time
`
`of the invention based on the combination of Tsien or Ju with Zavgorodny. 35
`
`U.S.C. § 316(e). IBS’s petition merely revisits the same references that the Patent
`
`Office fully considered during prosecution of the ’537 Patent, and over which the
`
`Examiner properly determined that Claims 1-6 and 8 were nonobvious. See, e.g.,
`
`’537 Patent Prosecution History Excerpts at 5 (Notice of Allowance, mailed April
`
`30, 2009, considering Zavgorodny), 10 (Office Action, mailed May 16, 2008,
`
`citing Tsien), and 20 (Office Action, mailed October 30, 2007, citing Ju) (Ex.
`
`2010). The Board should uphold the Examiner’s appropriate issuance of these
`
`claims over Tsien, Ju and Zavgorodny.
`
`IBS’s petition also fails to consider several important teachings in
`
`Zavgorodny that render his azidomethyl ether and removal conditions incompatible
`
`with Tsien and Ju’s express DNA sequencing requirements. In particular, IBS fails
`
`to consider that a person of ordinary skill in the art would have thought that:
`
`• Zavgorodny’s azidomethyl ether would interfere with DNA polymerases,
`
`• Zavgorodny’s removal conditions would not be quantitative or rapid,
`
`• Zavgorodny’s removal conditions would denature DNA, and
`
`
`
`-3-
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`
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`IPR2013-00517
`IBS v. Illumina
`
`
`• Zavgorodny’s azidomethyl ether would hinder reinitiation of DNA
`
`synthesis.
`
`For any one of the foregoing reasons, a person of ordinary skill in the art would not
`
`have been motivated to combine Tsien or Ju with Zavgorodny with a reasonable
`
`expectation of success. Furthermore, the patentability of the challenged claims is
`
`supported by several secondary considerations of nonobviousness, including long-
`
`felt but unsolved need, unexpected results, and copying by others. When one
`
`considers all of the relevant evidence, there is only one reasonable conclusion—
`
`Claims 1-6 and 8 of the ’537 Patent would not have been obvious to a person of
`
`ordinary skill in the art in August of 2002.
`
`II.
`
`Illumina’s Claimed Invention Includes a Novel, not Previously
`Considered 3’-OH Protecting Group for SBS
`
`In 1991, Tsien identified several criteria for a 3’-protecting group for use in
`
`DNA sequencing by synthesis (“SBS”). Tsien at 20:28-21:3, 23:27-24:5 (Ex.
`
`1008). With this information as a guide, researchers immediately set about
`
`identifying nucleotide 3’-protecting groups compatible with Tsien’s criteria. In
`
`1994, the search for the ideal 3’-protecting group was described as a “formidable
`
`obstacle.” Metzker et al., Nucl. Acids Res., 22:4259, 4259 (1994) (Ex. 2024,
`
`“Metzker”). The same remained true in 1999. Welch et al., Nucl. & Nucl., 18:197,
`
`
`
`-4-
`
`
`
`IPR2013-00517
`IBS v. Illumina
`
`197-198 (1999) (Ex. 2028, “Welch”). Even as late as 2004, Shendure3
`
`acknowledged
`
`that “developing reversible
`
`terminators with
`
`the necessary
`
`properties has proved to be a difficult problem.” Shendure et al., Nat. Rev. Gen.,
`
`5:335, 341 (2004) (Ex. 2029, “Shendure”).
`
`By August of 2002, at least 12 separate research groups had tried to find 3’-
`
`protecting groups that were ideal for use in DNA sequencing: (1) Tsien
`
`investigated at least 3’-O-allyl and various other groups (Tsien at 21:20-31; Ex.
`
`1008); (2) Canard investigated at least 3’-O-anthranyloyl and 3’-O-anthranyl
`
`derivatives (Canard et al., PNAS, 92:10859, 10859; Ex. 2019, “Canard”); (3)
`
`Dower contemplated at least “acetyl, tBOC, NBOC, and NVOC” 3’-OH protecting
`
`groups (U.S. 5,547,839 at 25:47-51; Ex. 2030); (4) Welch investigated 3’-O-(2-
`
`nitrobenzyl) groups with fluorescent labels (Welch at 198; Ex. 2028); (5) Stemple
`
`investigated at least 3’-O-(2-nitrobenzyl) groups (WO 00/53805 at 13:18-20; Ex.
`
`2031); (6) Odedra investigated at least acetyl and phenylacetamide groups (WO
`
`3 Shendure highlighted Solexa’s reversible terminators as “exciting” progress in the
`
`field due to “impressive signal-to-noise ratio.” Shendure at 341. Illumina acquired
`
`Solexa’s reversible terminator patent portfolio in 2006, including the reversible 3’-
`
`O-azidomethyl terminators that are the subject of this proceeding. Press Release,
`
`Illumina Signs Agreement to Acquire Solexa (Nov. 13, 2006) (Ex. 2078).
`
`
`
`-5-
`
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`
`IPR2013-00517
`IBS v. Illumina
`
`01/92284 at Figs. 2 & 11; Ex. 2032); (7) Metzker investigated 3’-O-methyl, 3’-O-
`
`acetyl,
`
`3’-O-allyl,
`
`3’-O-tetrahydropyran,
`
`3’-O-4-nitrobenzoyl,
`
`3’-O-2-
`
`aminobenzoyl, and 3’-O-2-nitrobenzyl groups (Metzker at 4263; Ex. 2024); (8)
`
`Cheeseman investigated at least 3’-O-succinyl and 3’-O-anhydride derivatives
`
`(U.S. 5,302509 at 4:50-63; Ex. 2033); (9) Kwiatkowski investigated at least 3’-O-
`
`hydrocarbyldithiomethyl and 3’-O-“functionalized acetal” groups (U.S. 7,279,563
`
`at 2:40-60, Ex. 2034; WO 96/023807 at 15:11-16:24, Ex. 2035); (10) Rosenthal
`
`investigated 3’-blocking groups that “generate a 3’ hydroxyl group” (WO
`
`93/21340 at 11:3-10; Ex. 2036); (11) Rabani investigated at least a 3’-O-(4-
`
`benzoyl)benzoyl group (WO 96/27025 at 2:15-21; Ex. 2037); and (12) Ju
`
`investigated at least 3’-O-allyl and 3’-O-methoxymethyl groups (see, e.g., Ju at
`
`Fig. 7 (Ex. 1002)). None of these researchers investigated or even suggested a
`
`protecting group comprising an azido group that can be modified or removed to
`
`expose a 3’-OH group.
`
`These research efforts showed that Tsien’s 3’-O-allyl group, as well as a few
`
`other groups, were reversible protecting groups that could be effectively
`
`incorporated by polymerases. Ex. 1008 at 24:29; Metzker at 4263 (Ex. 2024); Ju at
`
`3:7-22 (Ex. 1002); Manteia I at 9-12 (Ex. 2085); Manteia II at 6, 15 (Ex. 2086). Dr.
`
`Ju and Columbia University continued to use Tsien’s 3’-O-allyl group through at
`
`least 2006. Ju et al., PNAS, 103:19635 (2006) (Ex. 2038, “Ju PNAS”).
`
`
`
`-6-
`
`
`
`IPR2013-00517
`IBS v. Illumina
`
`
`Despite the aforementioned research efforts, only Illumina identified the
`
`azidomethyl group as a protecting group for DNA sequencing. ’537 Patent at
`
`19:49-20:4 (Ex. 1001). Illumina found that the azidomethyl protecting group was
`
`unexpectedly incorporated by polymerases and was surprisingly cleaved in rapid
`
`and quantitative yield under conditions that permit serial polymerase incorporation
`
`through numerous rounds of DNA sequencing. These properties were not known at
`
`the time the ’537 Patent was filed, and no knowledge in the art would have led a
`
`person of ordinary skill to expect that an azidomethyl group could be as successful
`
`as Illumina later demonstrated. Eisai Co. v. Dr. Reddy’s Labs., Ltd., 533 F.3d
`
`1353, 1359 (Fed. Cir. 2008). To date, Illumina’s 3’-O-azidomethyl group remains
`
`the unsurpassed industry leader even though 12 years have passed since the ’537
`
`Patent was filed.
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`Notably, IBS’s expert, Dr. Branchaud, was unaware of anyone other than
`
`Solexa suggesting the use of azidomethyl protecting groups until IBS/Ju started
`
`using them in 2008. Branchaud ‘517 Tr. at 162:12-163:22 (Ex. 2039); see also,
`
`infra Section X.3. But IBS/Ju’s first use of azidomethyl groups in SBS came many
`
`years after Solexa first published and suggested the use of azidomethyl groups in
`
`SBS (see, e.g., Guo et al., PNAS, 105:9145 (2008) (Ex. 2058)), and was not the
`
`result of independent invention, as discussed in detail infra. See, e.g., Section X.3;
`
`see also Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1353, 1359 (Fed. Cir.
`
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`IBS v. Illumina
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`2013). In view of the above, the nonobviousness of Illumina’s azido protecting
`
`group in Claims 1-6 and 8 of the ’537 Patent should be affirmed.
`
`III. The Law of Nonobviousness
`The petitioner bears the burden of proving obviousness. 35 U.S.C. § 316(e).
`
`The analysis under 35 U.S.C. § 103 is objective:
`
`[T]he scope and content of the prior art are to be determined;
`differences between the prior art and the claims at issue are to be
`ascertained; and the level of ordinary skill in the pertinent art
`resolved. Against this background the obviousness or nonobviousness
`of the subject matter is determined. Such secondary considerations as
`commercial success, long felt but unsolved needs, failure of others,
`etc., might be utilized to give light to the circumstances surrounding
`the origin of the subject matter sought to be patented.
`
`Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966).
`
`“[A] patent composed of several elements is not proved obvious merely by
`
`demonstrating that each of its elements was, independently, known in the prior
`
`art.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). Rather, there must be
`
`“an apparent reason to combine the known elements in the fashion claimed by the
`
`patent at issue.” Id. In other words, a patent claim is not obvious unless “a skilled
`
`artisan would have been motivated to combine the teachings of the prior art
`
`references to achieve the claimed invention, and that the skilled artisan would have
`
`had a reasonable expectation of success in doing so.” ActiveVideo Networks, Inc. v.
`
`
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`-8-
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`IPR2013-00517
`IBS v. Illumina
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`Verizon Commuc’ns, Inc., 694 F.3d 1312, 1327 (Fed. Cir. 2012).
`
`Moreover, the chemical arts are inherently unpredictable and, therefore, a
`
`reasonable expectation of success is harder to achieve. Eisai, 533 F.3d at 1359
`
`(“To the extent an art is unpredictable, as the chemical arts often are, KSR’s focus
`
`on these ‘identified predictable solutions’ may present a difficult hurdle because
`
`potential solutions are less likely to be genuinely predictable.”).
`
`“A factfinder should be aware, of course, of the distortion caused by
`
`hindsight bias and must be cautious of arguments reliant upon ex post reasoning.”
`
`KSR, 550 U.S. at 421 (citing Graham, 383 U.S. at 36). “It is difficult but necessary
`
`that the decisionmaker forget what he or she has been taught . . . about the claimed
`
`invention and cast the mind back to the time the invention was made (often as here
`
`many years), to occupy the mind of one skilled in the art . . . .” W.L. Gore &
`
`Assocs., Inc. v. Garlock, Inc., 721 F.2d 1540, 1553 (Fed. Cir. 1983).
`
`IV. The Person Of Ordinary Skill in the Art
`Illumina submits that the person of ordinary skill at the time of the invention
`
`would have been a member of a team of scientists addressing SBS product
`
`development. Such a person would have held a doctoral degree in chemistry,
`
`molecular biology, or a closely related discipline, and had at least five years of
`
`practical academic or industrial laboratory experience. Thus, a person of ordinary
`
`skill includes a person having a doctoral degree in a field related to chemistry, and
`
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`at least five years of laboratory experience directed toward the research and
`
`development of DNA sequencing technologies.4 Romesberg Decl. ¶ 26 (Ex. 2011).
`
`V. Grounds Of This Proceeding
`The Board instituted this proceeding on the following grounds:
`
`- Claims 1-6 and 8 under 35 U.S.C. § 103(a) over Tsien and Zavgorodny;
`
`- Claims 1-6 and 8 under 35 U.S.C. § 103(a) over Ju and Zavgorodny; and
`
`- Claim 3 under 35 U.S.C. § 103(a) over Tsien, Zavgorodny, and Prober.
`
`Paper 16 at 15. As detailed below, IBS has failed to meet its burden because its
`
`petition did not address several issues that would have led a person of ordinary
`
`skill in the art to expect that Zavgorodny’s removal conditions would be
`
`incompatible with the explicit requirements of Tsien and Ju’s DNA sequencing
`
`methods. Thus, the complete record shows that the labeling methods of Claims 1-6
`
`and 8 of the ’537 Patent would not have been obvious to one of ordinary skill in
`
`the art in view of Tsien or Ju in combination with Zavgorodny.
`
`
`4 IBS’s petition fails to address the level of ordinary skill in the art necessary to
`
`support its obviousness arguments. 35 U.S.C. § 103; Graham, 383 U.S. at 17.
`
`Thus, IBS’s assertions regarding the obviousness of Claims 1-6 and 8 of the ’537
`
`Patent lack foundation, and IBS fails to carry its burden in this proceeding.
`
`
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`-10-
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`IPR2013-00517
`IBS v. Illumina
`
`VI. Tsien’s 3’-Azido Group Cannot Be Removed To Expose A 3’-OH Group
`In instituting this proceeding, the Board states that “Tsien discloses using an
`
`azido-containing protecting group.” Paper 16 at 11 (citing Tsien at 21:12-17). The
`
`azido group disclosed in Tsien, however, is not a removable protecting group that
`
`will expose a 3’-OH group as required by Claims 1-6 and 8. Instead, the azido
`
`group disclosed by Tsien is a 3’-N3 blocking group that is directly attached to the
`
`3’-carbon of the nucleotide. Romesberg Decl. ¶ 39 (Ex. 2011). Because the Tsien
`
`N3 blocking group is directly attached to the 3’-carbon, its cleavage would not
`
`expose a 3’-OH group. Id. IBS’ expert, Dr. Branchaud, agrees and correctly
`
`testified that Tsien’s N3 group is not cleavable to expose a 3’-OH group:
`
`Q. Would a person of ordinary skill in the art have understood what
`the term “cleavable” meant at the time of the Tsien patent?
`A. I think there are a couple of different definitions of “cleavable.”
`That’s why I’m asking the question.
`Q. Okay. And what are those potential definitions?
`A. First -- okay. One is can you remove the group; the other is can the
`group be removed to leave a 3’ hydroxyl at that position. The second
`definition is relevant to this topic in general. The first one is more of
`just a general chemical question.
`Q. Yes. Okay. So using your second definition --
`A. Yes.
`Q. -- which of the blocking groups in Tsien are not cleavable?
`A. By that definition, it would be the F, the NH2, the N3, and the
`
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`IPR2013-00517
`IBS v. Illumina
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`
`NHCOCH3. The other ones would be cleavable by this second
`definition to leave a free 3’ hydroxyl.
`Q. Okay. Now, is the N3 group cleavable to regenerate a 3’-OH?
`A. If, as it’s stated here, the N3 is directly attached to the carbon,
`which is the way I read it, then that N3 group could be reacted
`chemically, but it would not generate a 3’ hydroxyl.
`
`Branchaud ‘128 Tr. at 100:1-101:6 (Ex. 2081) (emphases added). Dr. Romesberg
`
`confirms this admission by Dr. Branchaud. Romesberg Decl. ¶ 39 (Ex. 2011). For
`
`this reason, Tsien’s 3’-N3 blocking group does not teach an azido protecting group
`
`that can be modified or removed to expose a 3’-OH group.
`
`Furthermore, Tsien’s disclosure of the non-removable 3’-N3 blocking group
`
`is imbedded in a list of several other potential nucleotide blocking modifications,
`
`including other non-removable groups, such as –F, –NH2, and –NHCOCH3. Tsien
`
`at 21:12-17 (Ex. 1008); Romesberg Decl. ¶ 38 (Ex. 2011). Tsien provides no
`
`expectation that the 3’-N3 non-removable blocking group could ever be modified
`
`or removed to expose a 3’-OH group as required by Illumina’s claims. ’537 Patent
`
`at 19:57-58 (Ex. 1001). As a result, a person of ordinary skill in the art would not
`
`have been motivated to use the non-removable 3’-N3 group of Tsien to arrive at the
`
`instant claims.
`
`VII. Tsien’s Three 3’-Blocking Group Criteria Are Incompatible With
`Zavgorodny’s Azidomethyl Ether And Removal Conditions
`
`Tsien is directed to DNA sequencing by synthesis (“SBS”). IBS Revised
`
`
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`IPR2013-00517
`IBS v. Illumina
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`Petition at 12 (Paper 7); Branchaud Decl. ¶ 74 (Ex. 1011); Tsien at 6:26-7:3 (Ex.
`
`1008); Romesberg Decl. ¶ 36 (Ex. 2011). Tsien does not teach a protecting group
`
`comprising an azido group that can be modified or removed to expose a 3’-OH
`
`group. Nor would it have been obvious to the skilled artisan to combine Tsien with
`
`Zavgorodny to arrive at the claimed methods. One of ordinary skill in the art would
`
`not have been motivated to modify Tsien to incorporate Zavgorodny’s azido group
`
`because such a modification would not have been expected to work for its intended
`
`purpose. Institut Pasteur v. Focarino, 738 F.3d 1337, 1
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